Introduction: Accumulated evidence shows that the cAMP-PKA signaling pathway plays a key role in memory functions. Cyclooxygenase-2, a critical player in neuroinflammation, has been confirmed in the pathogenesis of neurodegenerative diseases. This study is aimed to assess the effect of the interaction of cAMP-PKA and cyclooxygenase pathways on spatial memory acquisition in animal models. Material and methods: In the present study, the effects of the four-day bilateral intra-hippocampal infusions of H-89 as a protein kinase AII inhibitor (10 μM/side), celecoxib (0.1 M/side) as a selective cyclooxygenase-2 inhibitor, celecoxib/H-89 and bucladesine (10 μM/side)/celecoxib/H-89 on spatial memory acquisition in the Morris water maze were investigated. Control animals received bilateral intra-hippocampal infusions of dimethyl sulfoxide. Rats were trained for 4 days; each day included one block of four trials. Post-training probe trial tests were performed on day five. Results: A bilateral intra-hippocampal infusion of H-89 and celecoxib led to a significant impairment in spatial learning compared to the controls through a notable decrease in escape latency and traveled distance. But, combination treatment of animals with celecoxib/H-89 and bucladesine/celecoxib/H-89 could considerably reverse celecoxib and H-89-induced spatial memory acquisition impairments in the Morris water maze. Conclusions: These results indicate the probable regulatory effects of cAMP/PKA and cyclooxygenase-2 signaling pathways on spatial memory acquisition in the Morris water maze.

Accumulated evidence shows that the cAMP and cGMP signaling pathway plays an important role in memory function and neuronal plasticity. Phosphodiesterase 5 (PDE5) is a hopeful therapeutic target in AD (Alzheimer disease), and PDE5 inhibition may be a good therapeutic strategy for the treatment of AD. In the present study, the four-day bilateral intra-hippocampal infusion of H-89 as a protein kinase AII inhibitor (10 µM/side) and intra-peritoneal injections of tadalafil (20 mg/kg) and scopolamine (0.5 mg/kg) alone and also on combination on spatial learning in Morris water maze (MWM) were investigated. DMSO and saline were used as controls for H-89 and other mentioned drugs, respectively. Rats were trained for 4 days; each day included one block of four trials. Post- training probe trial tests were performed on day 5. Administration of H-89 and scopolamine led to a significant impairment in spatial learning compared to their related controls. But, combination of tadalafil/H-89 or tadalafil/scopolamine reversed H-89 or scopolamine- induced spatial learning deficits in MWM. Taken together, these results showed the probable regulatory effects of cGMP on cholinergic and cAMP/PKA signaling pathways in co-administrations of these mentioned drugs on spatial learning in MWM.